title: NOTCH1, SF3B1, and TP53 mutations in fludarabine-refractory CLL patients treated with alemtuzumab: results from the CLL2H trial of the GCLLSG.
abstract: We studied the incidences, associations, and prognostic roles of NOTCH1 and SF3B1 mutations (NOTCH1(mut), SF3B1(mut)) as compared with TP53(mut) in fludarabine-refractory chronic lymphocytic leukemia (CLL) patients treated with alemtuzumab in the CLL2H trial. We found NOTCH1(mut), SF3B1(mut), and TP53(mut) in 13.4%, 17.5%, and 37.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) were mutually exclusive, whereas TP53(mut) were evenly distributed within both subgroups. Apart from correlation of SF3B1(mut) with 11q deletion (P = .029), there were no other significant associations of the mutations with any baseline characteristics or response rates. However, NOTCH1(mut) cases had a significantly longer progression-free survival (PFS) compared with wild-type cases (15.47 vs 6.74 months; P = .025), although there was no significant difference with overall survival (OS). SF3B1(mut) had no significant impact on PFS and OS. In multivariable analyses, NOTCH1(mut) was identified as an independent favorable marker for PFS. This clinical trial is registered at www.clinicaltrials.gov as #NCT00274976.
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schnaiter
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.forename: Marianna
authors.initials: M
authors.lastname: Rossi
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.forename: Andreas
authors.initials: A
authors.lastname: Bühler
authors.forename: Dirk
authors.initials: D
authors.lastname: Winkler
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Jennifer
authors.initials: J
authors.lastname: Edelmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Mertens
authors.forename: Sabrina
authors.initials: S
authors.lastname: Kless
authors.forename: Silja
authors.initials: S
authors.lastname: Mack
authors.forename: Raymonde
authors.initials: R
authors.lastname: Busch
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
mesh_terms: D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D010750:Phosphoproteins / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1 / Q000235:genetics*; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C497761:NOTCH1 protein, human; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000074323:Alemtuzumab; D014740:Vidarabine; C024352:fludarabine